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- PDB-4oty: Crystal structure of lumiracoxib bound to the apo-mouse-cyclooxyg... -

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Basic information

Entry
Database: PDB / ID: 4oty
TitleCrystal structure of lumiracoxib bound to the apo-mouse-cyclooxygenase-2
ComponentsProstaglandin G/H synthase 2
KeywordsOxidoreductase/Oxidoreductase inhibitor / protein-drug complex / OXIDOREDUCTASE / NSAIDS / HEME / GLYCOSYLATION / MONOTOPIC MEMBRANE PROTEIN / drug complex / Oxidoreductase-Oxidoreductase inhibitor complex
Function / homology
Function and homology information


Biosynthesis of DHA-derived SPMs / Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives / Synthesis of 15-eicosatetraenoic acid derivatives / cellular response to non-ionic osmotic stress / : / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / prostaglandin-endoperoxide synthase / prostaglandin-endoperoxide synthase activity ...Biosynthesis of DHA-derived SPMs / Biosynthesis of EPA-derived SPMs / Biosynthesis of DPAn-3 SPMs / Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives / Synthesis of 15-eicosatetraenoic acid derivatives / cellular response to non-ionic osmotic stress / : / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / prostaglandin-endoperoxide synthase / prostaglandin-endoperoxide synthase activity / cyclooxygenase pathway / negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress / positive regulation of prostaglandin biosynthetic process / regulation of neuroinflammatory response / response to selenium ion / positive regulation of fever generation / prostaglandin secretion / cellular response to fluid shear stress / response to nematode / nuclear inner membrane / prostaglandin biosynthetic process / dioxygenase activity / bone mineralization / nuclear outer membrane / decidualization / brown fat cell differentiation / keratinocyte differentiation / positive regulation of brown fat cell differentiation / embryo implantation / peroxidase activity / regulation of blood pressure / regulation of cell population proliferation / cellular response to hypoxia / response to oxidative stress / neuron projection / heme binding / endoplasmic reticulum membrane / negative regulation of apoptotic process / enzyme binding / protein homodimerization activity / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / Myeloperoxidase, subunit C / Haem peroxidase domain superfamily, animal type / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / Laminin / Laminin / EGF-like domain ...: / Myeloperoxidase, subunit C / Haem peroxidase domain superfamily, animal type / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / Laminin / Laminin / EGF-like domain / Haem peroxidase superfamily / EGF-like domain profile. / EGF-like domain / Ribbon / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-LUR / Prostaglandin G/H synthase 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.354 Å
AuthorsXu, S. / Windsor, M.A. / Banerjee, S. / Marnett, L.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.
Authors: Windsor, M.A. / Valk, P.L. / Xu, S. / Banerjee, S. / Marnett, L.J.
History
DepositionFeb 14, 2014Deposition site: RCSB / Processing site: RCSB
SupersessionFeb 26, 2014ID: 4LLZ
Revision 1.0Feb 26, 2014Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 27, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Prostaglandin G/H synthase 2
B: Prostaglandin G/H synthase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,27911
Polymers134,6652
Non-polymers2,6139
Water5,531307
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8170 Å2
ΔGint15 kcal/mol
Surface area42840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.663, 133.173, 181.546
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Prostaglandin G/H synthase 2 / Cyclooxygenase-2 / COX-2 / Glucocorticoid-regulated inflammatory cyclooxygenase / Gripghs / ...Cyclooxygenase-2 / COX-2 / Glucocorticoid-regulated inflammatory cyclooxygenase / Gripghs / Macrophage activation-associated marker protein P71/73 / PES-2 / PHS II / Prostaglandin H2 synthase 2 / PGH synthase 2 / PGHS-2 / Prostaglandin-endoperoxide synthase 2 / TIS10 protein


Mass: 67332.711 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 / Plasmid: pVL-1393 / Cell line (production host): Sf21 / Production host: homo sapiens (human)
References: UniProt: Q05769, prostaglandin-endoperoxide synthase

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Sugars , 3 types, 7 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0

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Non-polymers , 2 types, 309 molecules

#4: Chemical ChemComp-LUR / {2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}acetic acid / Lumiracoxib


Mass: 293.721 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H13ClFNO2 / Comment: antiinflammatory, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 307 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.75 Å3/Da / Density % sol: 55.32 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
Details: mCOX-2 protein reconstituted with a 2-fold molar excess of heme in phosphtate buffer, pH 6.7, 100 mM NaCl, 1.2% (w/v) -OG, and 0.1% NaN3, and 10-fold molar excess of inhibitors from 25 mM ...Details: mCOX-2 protein reconstituted with a 2-fold molar excess of heme in phosphtate buffer, pH 6.7, 100 mM NaCl, 1.2% (w/v) -OG, and 0.1% NaN3, and 10-fold molar excess of inhibitors from 25 mM DMSO stocks were added to protein samples. Mixing 3 uL of the protein-inhibitor complex with 3 uL crystallization solution containing 50 mM EPPS, pH 8.0, 120 mM MgCl2, 22-26% PEG MME-550 against reservoir solutions comprised of 50 mM EPPS pH 8.0, 120 mM MgCl2, 22-26% PEG MME-550, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 5, 2012
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. all: 61558 / Num. obs: 61543 / % possible obs: 99.64 % / Observed criterion σ(F): 1.36 / Observed criterion σ(I): 1 / Redundancy: 5.8 % / Biso Wilson estimate: 52.746 Å2 / Rmerge(I) obs: 0.073 / Net I/σ(I): 6.7
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.493 / Mean I/σ(I) obs: 6.7 / Num. unique all: 5978 / % possible all: 98

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8.4_1496)refinement
XDSdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 3NT1

3nt1


Resolution: 2.354→43.121 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 1876 3.05 %RANDOM
Rwork0.1798 ---
obs0.1811 61543 99.61 %-
all-61558 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.354→43.121 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8939 0 172 307 9418
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0079385
X-RAY DIFFRACTIONf_angle_d0.81512725
X-RAY DIFFRACTIONf_dihedral_angle_d13.6183461
X-RAY DIFFRACTIONf_chiral_restr0.0461366
X-RAY DIFFRACTIONf_plane_restr0.0041640
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3538-2.41740.28571220.24784409X-RAY DIFFRACTION96
2.4174-2.48860.30341380.23834509X-RAY DIFFRACTION100
2.4886-2.56890.29131310.22454595X-RAY DIFFRACTION100
2.5689-2.66070.28671300.22314585X-RAY DIFFRACTION100
2.6607-2.76720.26611340.21974558X-RAY DIFFRACTION100
2.7672-2.89310.26671500.22064562X-RAY DIFFRACTION100
2.8931-3.04560.27691650.21914585X-RAY DIFFRACTION100
3.0456-3.23630.25621540.21194563X-RAY DIFFRACTION100
3.2363-3.48610.25511620.19754583X-RAY DIFFRACTION100
3.4861-3.83680.19821370.16454612X-RAY DIFFRACTION100
3.8368-4.39150.17711540.14864636X-RAY DIFFRACTION100
4.3915-5.5310.18571540.1434667X-RAY DIFFRACTION100
5.531-43.12790.19881450.16754803X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.149-0.0578-0.1627-0.0557-0.07830.4756-0.05310.36750.7171-0.05330.0041-0.2038-0.558-0.1009-0.04380.5943-0.1009-0.02890.2620.13720.8141-25.676664.170131.5233
20.01770.0078-0.0450.0425-0.02170.0088-0.1490.15770.22570.1442-0.0234-0.1558-0.18320.2917-00.4833-0.1237-0.03010.62620.15780.5701-2.340748.128328.8831
30.40460.02830.1696-0.05560.18590.28660.02490.11340.15990.0488-0.0611-0.0083-0.09590.061100.31670.02670.01710.2920.0430.2813-31.675241.910726.1587
40.8988-0.27640.26340.15230.01720.85120.05310.22610.02020.0533-0.0006-0.0010.04110.185800.29370.018-0.00340.30230.02790.2668-19.504630.981727.9061
50.1112-0.08230.22160.0134-0.01540.30470.0397-0.03390.22440.32350.0799-0.14930.29610.4893-0.00280.38380.0042-0.04160.59-0.07910.5475-1.277137.911263.2636
60.0237-0.00550.01760.0343-0.00830.0847-0.29750.18380.39620.0830.0652-0.0368-0.26870.1631-0.20490.5025-0.0567-0.27180.5285-0.16420.8583-14.990462.408965.5363
70.12860.0422-0.01780.01820.00020.0313-0.0502-0.07640.0325-0.1079-0.01990.07430.30040.190500.39240.0539-0.04150.3692-0.00340.2827-18.111628.017165.4098
80.05480.1315-0.11790.644-0.25430.1298-0.1304-0.42330.2887-0.3672-0.11240.08580.1793-0.0528-0.07860.27210.00980.00010.6256-0.15530.291-32.578142.634673.7845
90.518-0.18550.4220.44470.00250.4683-0.035-0.29060.2406-0.1118-0.0127-0.0327-0.011-0.1123-0.00360.25360.002-0.01730.2861-0.09630.3231-39.538948.566359.6827
100.02040.014-0.0380.0157-0.02420.02-0.1445-0.55410.0867-0.02280.07040.2056-0.0089-0.382100.44480.0514-0.02140.9901-0.17830.4336-46.743347.98280.3527
110.310.2425-0.19010.1563-0.16310.343-0.1316-0.3474-0.07680.11260.0269-0.10480.28570.0504-0.04720.45490.005-0.0750.6126-0.09370.3307-19.234836.630678.0541
120.43570.01660.30211.0241-0.50841.3453-0.161-0.25241.0246-0.2498-0.5706-0.74790.08090.3965-0.61220.1829-0.0595-0.16630.2704-0.36960.2673-26.035349.933568.5386
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 33 through 93 )
2X-RAY DIFFRACTION2chain 'A' and (resid 94 through 123 )
3X-RAY DIFFRACTION3chain 'A' and (resid 124 through 218 )
4X-RAY DIFFRACTION4chain 'A' and (resid 219 through 583 )
5X-RAY DIFFRACTION5chain 'B' and (resid 33 through 93 )
6X-RAY DIFFRACTION6chain 'B' and (resid 94 through 123 )
7X-RAY DIFFRACTION7chain 'B' and (resid 124 through 181 )
8X-RAY DIFFRACTION8chain 'B' and (resid 182 through 218 )
9X-RAY DIFFRACTION9chain 'B' and (resid 219 through 390 )
10X-RAY DIFFRACTION10chain 'B' and (resid 391 through 428 )
11X-RAY DIFFRACTION11chain 'B' and (resid 429 through 485 )
12X-RAY DIFFRACTION12chain 'B' and (resid 486 through 582 )

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